PPAR is known as one of nuclear receptor families, and three subtypes (α, γ, δ) thereof are so far known to exist (Non-Patent Documents 1 to 5). Among these, PPARα is mainly expressed in the liver, and is known to be activated by plasticizers and fibrate drugs, for example, Wy14643 or drugs that are already being marketed as pharmaceutical products, such as clofibrate, fenofibrate, bezafibrate, gemfibrozil and the like (Non-Patent Documents 6 to 7).
Activation of PPARα is known to cause an increase in β-oxidation of fatty acids, and a decrease in the blood triglyceride level in mammals, and to reduce the blood lipid such as low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, and the like, in humans Thus, PPARα activators are believed to be useful as a prophylactic and/or therapeutic agent for hyperlipidemia and the like. Furthermore, since PPARα activators increase high density lipoprotein (HDL) cholesterol, while suppressing the expression of VCAM-1, which is a cell adhesion factor in the blood vessel, the activators are considered to be useful as a prophylactic and/or therapeutic agent for arteriosclerosis and the like, and useful for the prevention and/or treatment of diabetes mellitus, inflammatory diseases, heart diseases and the like (Non-Patent Documents 8 to 14).
Meanwhile, activation of PPARγ causes an increase in fats in humans, and is reported to have an undesirable action of inducing weight increase or obesity (Non-Patent Document 15). Recently, it has been also reported that there is a possibility to improve resistance to insulin by means of PPARγ antagonists (Non-Patent Documents 16 to 18). Also, it is suggested that activation of PPARδ is connected with the action of lipid accumulation (Non-Patent Document 19). Therefore, it is conceived that PPARα-selective activators having low activities for PPARγ and PPARδ are useful as prophylactic and/or therapeutic agents for hyperlipidemia, arteriosclerosis, diabetes mellitus, diabetic complications, inflammation, heart diseases and the like, without being accompanied by weight increase or obesity.
Under such circumstances, the inventors of the present invention found that a compound represented by the following Formula (A):
wherein R1 and R2, which may be identical or different, each represent a hydrogen atom, a methyl group or an ethyl group; R3a, R3b, R4a and R4b, which may be identical or different, each represent a hydrogen atom, a halogen atom, a nitro group, a hydroxyl group, a C1-4 alkyl group, a trifluoromethyl group, a C1-4 alkoxy group, a C1-4 alkylcarbonyloxy group, a di-C1-4 alkylamino group, a C1-4 alkylsulfonyloxy group, a C1-4 alkylsulfonyl group, a C1-4 alkylsulfinyl group or a C1-4 alkylthio group, or alternatively, R3a and R3b or R4a and R4b are bound to represent an alkylenedioxy group; X represents an oxygen atom, a sulfur atom or N—R5 (wherein R5 represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkylsulfonyl group or a C1-4 alkyloxycarbonyl group); Y represents an oxygen atom, a S(O)1 group (wherein 1 represents a number from 0 to 2), a carbonyl group, a carbonylamino group, an aminocarbonyl group, a sulfonylamino group, an aminosulfonyl group or an NH group; Z represents CH or N; n represents a number from 1 to 6; and m represents a number from 2 to 6,
or a salt thereof selectively activates PPARα, thus being useful as a medicine, and filed a patent application (Patent Document 1).
[Patent Document 1] PCT/JP04/012750
[Non-Patent Document 1] Nature, 347, 645-650, 1990
[Non-Patent Document 2] Cell, 68, pp. 879-887, 1992
[Non-Patent Document 3] Cell, 97, pp. 161-163, 1999
[Non-Patent Document 4] Biochim. Biophys. Acta., 1302, pp. 93-109, 1996
[Non-Patent Document 5] Journal of Medicinal Chemistry, 43, pp. 527-550, 2000
[Non-Patent Document 6] Journal of the National Cancer Institute, 90, 1702-1709, 1998
[Non-Patent Document 7] Current Opinion in Lipidology, 10, pp. 245-257, 1999
[Non-Patent Document 8] Journal of Atherosclerosis and Thrombosis, 3, pp. 81-89, 1996
[Non-Patent Document 9] Current Pharmaceutical Design, 3, pp. 1-14, 1997
[Non-Patent Document 10] Current Opinion in Lipidology, 10, pp. 151-159, 1999
[Non-Patent Document 11] Current Opinion in Lipidology, 10, pp. 245-257, 1999
[Non-Patent Document 12] The Lancet, 354, pp. 141-148, 1999
[Non-Patent Document 13] Journal of Medicinal Chemistry, 43, pp. 527-550, 2000
[Non-Patent Document 14] Journal of Cardiovascular Risk, 3, pp. 195-201, 2001
[Non-Patent Document 15] The Lancet, 349, pp. 952, 1997
[Non-Patent Document 16] Proc. Natl. Acad. Sci., 96, pp. 6102-6106, 1999
[Non-Patent Document 17] The Journal of Biological Chemistry, 275, pp. 1873-1877, 2000
[Non-Patent Document 18] J. Clin. Invest., 108, 1001-1013, 2001
[Non-Patent Document 19] Proc. Natl. Acad. Sci., 99, pp. 303-308, 2002